We have recently discovered the activity-dependent, intracellular O-GlcNAcylation of MeCP2 in embryonic cortical neurons. This research proposal aims to 1) identify which amino acids of MeCP2 are O- GlcNAcylated and 2) determine the functional significance of O-GlcNAc-MeCP2. We hypothesize that following seizure, MeCP2 O-GlcNAcylation triggers the dissociation of MeCP2 from certain gene promoters it is involved in repressing, thereby triggering the expression of those genes. This finding will further the understanding of the molecular mechanisms governing Rett syndrome, a common form of female mental retardation that is characterized by postnatal onset and seizures, and caused by loss of MeCP2 function.